Ulcerative colitis (UC) is a chronic tissue-destructive disease in which cellular inflammation and inflammatory cytokines ultimately lead to damage of the colonic mucosa. There is no effective cure, and while standard therapies can ameliorate symptoms in some patients, they are not effective in a significant number of patients and can also cause severe side effects. Consequently, new therapeutic approaches are needed to inhibit the inappropriate and exaggerated inflammatory response in UC patients. The new therapeutic target that this application will develop is based on the recent elucidation of the "inflammatory reflux" in which the nervous system through the vagus nerve regulates immune responses by release of acetylcholine which binds to macrophage a7 nicotinic acetylcholine receptors nAChR resulting in inhibition of inflammatory cytokine production. The goal of this proposal is to evaluate a panel of partial agonists selective for the a7 nicotinic acetylcholine receptor to determine the best drug candidate for further preclinical development. GTS-21 and its three biologically active metabolites will be evaluated in vivo for their ability to ameliorate development of disease symptoms and colon pathological changes in the murine ozaxolone-induced colitis model, which resembles human UC. Drugs will be tested in both prophylactic and therapeutic (administered after initiation of colitis) protocols. Drug efficacy will be monitored by weight loss, stool consistency and presence of blood, histopathology of the colon, and colon tissue content of myeloperoxidase. To investigate the mechanism of action, we will test the hypothesis that the GTS compounds will modulate the production of pathogenic and/or protective cytokines in the inflamed colon and isolated mononuclear cells. The results of this study will determine the best drug candidate for further preclinical and clinical development. Because the a7 nAChR agonists will inhibit production of multiple inflammatory cytokines known to be responsible, at least in part, for damage to colonic mucosa, this therapeutic approach should be more effective than other biological therapies that target only one cytokine. Ultimately this work will develop a new therapeutic option for ulcerative colitis patients that is based on a novel anti-inflammatory pathway that may be superior to current treatments. PUBLIC HEALTH RELEVANCE: This work will develop a new therapeutic option for ulcerative colitis patients that is based on a novel anti-inflammatory pathway that may be superior to current therapies. [unreadable] [unreadable] [unreadable]